Isolation and Characterization of Isofraxidin 7- O

Abnormalities in skin pigmentation can produce disorders such as albinism or melasma. There is a research need to discover novel compounds that safely and effectively regulate pigmentation. To identify novel modulators of pigmentation, we attempted to purify compounds from a bioactive fraction of the Korean medicinal plant Artemisia capillaris Thunberg. The novel compound isofraxidin 7-O-(6′-O-p-coumaroyl)-β-glucopyranoside (compound 1) was isolated and its pigmentation activity was characterized in mammalian melanocytes. Compound 1 stimulated melanin accumulation and increased tyrosinase activity, which regulates melanin synthesis. Moreover, compound 1 increased the expression of tyrosinase and the key melanogenesis regulator microphthalmia-associated transcription factor (MITF) in melanocytes. Compared to the parent compound, isofraxidin, compound 1 produced greater effects on these pigmentation parameters. To validate compound 1 as a novel hyperpigmentation agent in vivo, we utilized the zebrafish vertebrate model. Zebrafish treated with compound 1 showed higher melanogenesis and increased tyrosinase activity. Compound 1 treated embryos had no developmental defects and displayed normal cardiac function, indicating that this compound enhanced pigmentation without producing toxicity. In summary, our results describe the characterization of novel natural product compound 1 and its bioactivity as a pigmentation enhancer, demonstrating its potential as a therapeutic to treat hypopigmentation disorders

ENOblock inhibits the pathology of diet-induced obesity

Abstract Obesity is a medical condition that impacts on all levels of society and causes numerous comorbidities, such as diabetes, cardiovascular disease, and cancer. We assessed the suitability of targeting enolase, a glycolysis pathway enzyme with multiple, secondary functions in cells, to treat obesity. Treating adipocytes with ENOblock, a novel modulator of these secondary ‘moonlighting’ functions of enolase, suppressed the adipogenic program and induced mitochondrial uncoupling. Obese animals treated with ENOblock showed a reduction in body weight and increased core body temperature. Metabolic and inflammatory parameters were improved in the liver, adipose tissue and hippocampus. The mechanism of ENOblock was identified as transcriptional repression of master regulators of lipid homeostasis (Srebp-1a and Srebp-1c), gluconeogenesis (Pck-1) and inflammation (Tnf-α and Il-6). ENOblock treatment also reduced body weight gain, lowered cumulative food intake and increased fecal lipid content in mice fed a high fat diet. Our results support the further drug development of ENOblock as a therapeutic for obesity and suggest enolase as a new target for this disorder

GPR182 is an endothelium-specific atypical chemokine receptor that maintains hematopoietic stem cell homeostasis

G protein–coupled receptor 182 (GPR182) has been shown to be expressed in endothelial cells; however, its ligand and physiological role has remained elusive. We found GPR182 to be expressed in microvascular and lymphatic endothelial cells of most organs and to bind with nanomolar affinity the chemokines CXCL10, CXCL12, and CXCL13. In contrast to conventional chemokine receptors, binding of chemokines to GPR182 did not induce typical downstream signaling processes, including Gq- and Gi-mediated signaling or β-arrestin recruitment. GPR182 showed relatively high constitutive activity in regard to β-arrestin recruitment and rapidly internalized in a ligand-independent manner. In constitutive GPR182-deficient mice, as well as after induced endothelium-specific loss of GPR182, we found significant increases in the plasma levels of CXCL10, CXCL12, and CXCL13. Global and induced endothelium-specific GPR182-deficient mice showed a significant decrease in hematopoietic stem cells in the bone marrow as well as increased colony-forming units of hematopoietic progenitors in the blood and the spleen. Our data show that GPR182 is a new atypical chemokine receptor for CXCL10, CXCL12, and CXCL13, which is involved in the regulation of hematopoietic stem cell homeostasis.ISSN:0027-8424ISSN:1091-649